New aminomethyl-steroids and process for their manufacture



United States Patent Qfiice $33,854 Patented May 8, 19562 3,033,854 NEWAMTNGMETHYL-STERUTBS AND PROCEfifi FQR THEIR MANUFACTURE AlbertEschenmoser, Zurich, Switzerland, assignor to Ciba PharmaceuticalProducts Inc., Summit, NJ. No Drawing. Filed Feb. 9, 1960, Ser. No.7,529 Claims priority, application Switzerland Feb. 10, 1959 Claims.(Cl. 260-2395) in which R and R represent alkyl radicals or il -FR standfor an alkyleue radical.

According to the present process the M-Z-hydroxymethylene-3-kctosteroidsused as starting materials are reacted with a secondary aliphatic orcycloaliphatic amine, for example with dimethylamine, diethylamine, ormore especially With pyrrolidine, piperidiue or the like. The reactionis advantageously carried out in a suitable diluent, for example in anorganic solvent such as an alcohol, ether, hydrocarbon, or in a mixtureof two or more such solvents, or in an excess of amine, and thetemperature used may range, for example, from C. to 150 C. It is easy tofollow the progress of the reaction by measuring the ultravioletabsorption. The Z-enarnines formed display a characteristic ultravioletabsorption at about 380 mu.

The reduction of the Z-enamine formed may be carried out with a metalhydride, more especially one of the type of lithium aluminum hydride orlithium tritertiary butoxy aluminum hydride of which an excess isadvantageously used. The reduction is performed in the presence of asuitable solvent that is inert towards the reducing agent, for examplein an ether such as diethyl ether, dioxane or tetrahydrofuran,advantageously at a temperature between room temperature and the boilingtemperature of the solvent employed. Surprisingly, it has beenobservedthat the A -3-keto grouping is not reduced, although an excess of metalhydride is used. Ketalized keto groups, for example in the 20-position,are hydrolysed after the reduction with the metal hydride in the knownmanner, for example with an acid, such as acetic acid,para-toluenesulfonic acid or perchloric acid.

The new A -2-secondary aminomethyl-S-keto-steroids obtained as finalproducts can be converted in the known manner into their salts, such ashydrochlorides, sulfates, tartrates, citrates or the like.

The A -2-hydroxymethylene-3-keto-steroids used as starting materials maybelong to any one of the following series: cholestane, sitostane,ergostane, spirostane, cholane, nor-cholane, bis-nor-cholane, pregnaneor androgroups are reduced to hydroxyl groups, free and functionallyconverted carboxyl groups are converted into hydroxymethyl groups. andethinyl groups into vinyl groups. Specific starting materials are, forexample, the Z-hydroxymethylene compounds of testosterone,17amethyi-testosterone, 17a-ethinyl-testosterone, progesteroneand17a-acetoxy-progesterone-ZO-monoethylene ketal,cortisone-l7:20;20:2l-bismethylene ketal, A cholesterone andA=-3-ketospirostene.

The products of the invention display biological action or can be usedas intermediates in the manufacture of therapeutically active compounds.Thus for example the 2-pyrrolidinomethyl-testosterone shows an 'anaboleaction.

Particular mention deserve the 2-secondary aminomethyl compounds, forexample the 2-pyrrolidino-methy1 compounds of testosterone,l7a-methyl-testosterone, progesterone, 17a-acetoxy-progesterone,cortisone, cholestenone and A -3-keto-spirostene.

The following examples illustrate the invention:

xampie 1 5 grams of A -2-1ydroxymethylene-3-keto-cholestene aredissolved in 100 cc. of methanol, 100 cc. of pyrrolidine are added, andthe mixture is kept for 18 hours at 20 C. The solvent, together with theexcess pyrrolidine,

is distilled oil? in vacuo at 40 C., and the residue is restane. Apartfrom those mentioned above, these starting peatedly evaporated withbenzene and then recrystallized from petroleum ether. A-2-pyrrolidinomethylene-3-ketochole'stene, which is obtained in a yieldof to melts at ll81l9 C. and displays in the ultraviolet absorptionspectrum maxima at 25 1' Ina/log (5:423 and at 380 mil/10g 5:4.15.

3 grams of the Z-enamine obtained in this manner are dissolved in 200cc. of absolute ether, added dropwise to a vibrated suspension of 3grams of lithiumaluminum hydride in 200 cc. of absolute ether, and theWhole is heated for 4 hours at 35 C. The reaction mixture is stronglycooled, treated with saturated Seignette salt solution and diluted withether. The ethereal layer is washed with water until neutral, dried overanhydrous sodium sulfate and evaporated in vacuo. The resulting residueis a colorless oil which does not crystallize. The infrared spectrum ofthe compound contains the double bond of the cue-unsaturated ketone at6.02 and at 6.16

To prepare the pure 2-pyrrolidinomethyl compound the crude reactionproduct is dissolved in absolute ether and While being cooled with iceneutralized with an alcoholic hydrogen chloride solution. The solvent isevaporated and the resulting hydrochloride of A -2-pyrrolidinomethyl Y3-keto-cholestene is crystallized from acetone. It melts Example 2 2grams of Z-hydroxymethylene-testosterone are dissolved in cc. of benzeneand boiled with 1 gram of pyrrolidine for 2 hours in a Water separator.A further 1 gram of pyrrolidine is added and the whole is heated foranother hour. The benzene and the excess of pyrrolidine are evaporatedin a water-jet vacuum. The crude product (2.6 grams) displays in theultraviolet absorption spectrum maxima at 251 m t/log s=4.15 and at 380HIM/10g e=4.l1. It can be subjected to reduction without requiringprevious purification.

A solution of the crude Z-enamine in 100 cc. of tetrahydrofuran isslowly stirred dropwise into a suspension of 2 grams of lithium aluminumhydride in cc. of ether. The Whole is refluxed for 3 hours, and thereaction mixture is then cooled with ice+sodium chloride cooling mixtureand decomposed with saturated Seignette aoaeess testosterone, melting at190-192 C. with decomposition.

Optical rotation [a] =+4Q.

Example 3 1 gram of Z-hydroxymethylene-17a-methyl-testosterone isdissolved 'in 30 cc. of ether with the addition of 1 gram ofpyrrolidine,and the whole is refluxed for 3 hours. Evaporation of the reactionsolution in a water jet vacuum yields a dark yellow oil; its ultravioletabsorption spectrum reveals the presence of practically pure 2pyrrolidiuomethylene 17oz methyl testosterone. k =251 m log 6=4.17; 380m log 35:413.

'The crude Z-enamine is dissolved in 50 cc. of dioxane and addeddropwise to a suspension of 1 gram of lithium aluminum hydride in 50 cc.of ether and 50 cc.'of diox ane. While being vigorously stirred thereaction mixture is refluxed for 1 hour and then worked up with theaddi- -tion of ether and saturated Seignette salt solution as describedin Examples 1 and 2. In this manner2-pyrrolidinomethyl-l7u-methyl-testosterone can be isolated in a yieldof 30%. Melting point 168-172 C. (with decomposition). The melting pointdepends largely on the rapidity of the determination.

, Example 4 V V 1 gram of 2-hydroxymethylene-17:20;20:21-bis-meth- 4 abands of the M-S-keto-Z-enamines at 250 mu, log e=4.l5 and at 380 m log6 4.1. It can be subjected to the reduction without previouspurification.

A solution of the crude Z-enamine in 100 cc. of tetrahydrofuran is addeddropwise to a vibrated suspension of2 grams of lithium aluminum hydridein 100 cc. of

V ether, and the whole is then refluxed for 3 hours. Whileylenedioxy-cortisone is reacted with 200 cc. of pyrrolidine r andstirred for 18 hours'at 20 C. After repeatedly evaporating the reactionmixture withbenzene in vacuo, a brown oil is obtained which crystallizesin yellow prisms on being sprinkled with methanol. The ultravioletspectrum of the crude product contains the characteristic cooling thereactionsolution, it is treated with saturated Seignette salt solution,diluted with ether, washed until neutral, dried and evaporated at 30 C.in vacuo. The distillation residue is a pale-yellow, partiallycrystalline oil. Recrystallization from methylene chloride-kpetroleumether yields theZ-pyrrolidiuomethyl-17:20;20:2lbis-methylenedioXy-cortisone which meltsat 19S-l98 C. with decomposition and, on being subjected to ketalcleavage with para-toluenesulfonic acid in acetone at room temperature,yields 2-pyrrolidinomethyl-cortisone.

What is claimed is: V

1. Process for the manufacture of aminomethylsteroids, wherein a A-2-hydroxymethylene3-keto-steroid is reacted with a member selected fromthe group consisting of a secondary aliphatic amine and a secondarycycloaliphatic amine and the resulting 2-enamine reduced with a memberselected from the group consisting of an aluminum alkali metal complexhydride and an alkoxy derivative thereof, any ketalized keto groupspresent hydrolysed, and the resulting amine converted into athetapeutically useful acid addition salt thereof.

2. Process as claimed in claim 1, wherein pyrrolidine is used assecondary amine.

3. Process as claimed in claim 1, wherein lithium aluminum hydride isused for the reduction of the 2-enamine.

4. -2-pyrrolidinomethyl testosterone and its therapeuti cally usefulacid addition salts.

. 923-24, July 18, 1959.

1. PROCESS FOR THE MANUFACTURE OF AMINOMETHYLSTERIODS, WHEREIN A $4-2-HYDROXYMETHYLENE-3KETO-STERIOD IS REACTED WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF A SECONDARY ALIPHATIC AMINE AND A SECONDARY CYCLOALIPATIC AMINE AND THE RESULTING 2-ENAMINE REDUCED WITH A MEMBER SELECTED FROM THE GROUP CONSISTING AN ALUMINUM ALKALI METAL COMPLEX HYDRIDE AND AN ALKOXY DERIVATIVE THEREOF, ANY KETALIZED KETO GROUPS PRESENT HYDROLYSED, AND THE RESULTING AMINE CONVERTED INTO A THERAPEUTICALLY USEFUL ACID ADDITION SALT THEREOF.
 4. 2-PYRROLIDINOMETHYL TESTOSTERONE AND ITS THERAPEUTICALLY USEFUL ACID ADDITION SALTS. 